IL-9 signaling enhances CAR T cell antitumor efficacy in solid tumors by promoting memory phenotypes and reducing dysfunction under antigen stress 2144

Abstract Description Chimeric antigen receptor (CAR) T cell therapy has shown high efficacy for the treatment of blood cancers, but its success in treating solid tumors remains limited. Here, we have engineered CAR T cells targeting the tumor antigen mesothelin to express an interleukin-9 receptor (IL-9R), providing them with an IL-9 signal (CAR-IL9R T cells). IL-9R is expressed on various immune cells, but its role in T cells is a gap in knowledge in the field. To investigate the impact of IL-9 signaling in CAR T cell antitumor efficacy, we used a xenograft model of pancreatic ductal adenocarcinoma. IL-9-signaling CAR T cells outperformed conventional CAR T cells, leading to enhanced tumor control, prolonged overall survival, and improved CAR T cell expansion. Tumor re-challenge studies showed increased CAR T cell persistence, and a tumor harvest revealed higher CAR T cell infiltration with a central memory phenotype and reduced expression of co-inhibitory receptors. In an in vitro dysfunction model, IL-9 signaling preserved CAR T cell function and a central memory phenotype after repeated antigen exposure. Single-cell RNA sequencing revealed that IL-9 signaling alters CAR T cell fates under antigen stress, favoring the transition of CD8+ cells toward memory states and reducing progression to dysfunctional states, while promoting proliferative cycling in CD4+ cells. Together, this work highlights IL-9 signaling as a promising strategy for enhancing CAR T cell efficacy against solid tumors. Funding Sources Supported by PCF Tactical Grant, The Mark Foundation, Parker Institute for Cancer Immunotherapy RISE Scholar Award Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)